Optically active α-aminonitrile and process for producing α-amino acid

ABSTRACT

An aldehyde compound is reacted with an amino compound and hydrogen cyanate in the presence of a chiral zirconium catalyst obtained by mixing a zirconium alkoxide with an optically active binaphthol compound.

TECHNICAL FIELD

The present invention relates to a method for producing optically activeα-aminonitriles and α-amino acids. More specifically, the inventionrelates to a novel method, which enables the synthesis of opticallyactive α-aminonitriles followed by the synthesis of optically activeα-amino acids in high yield and high stereoselectivity.

BACKGROUND ART

Various α-amino acids and α-aminonitriles, as intermediates thereof, areuseful substances in various fields such an pharmaceuticals,agricultural chemicals, toiletries and other such chemical products, anwell an in the fold of functional polymers.

With respect to the synthesis of these useful substances, lately, therehave been some reports on the method of catalytic asymmetric synthesisof α-aminonitriles.

However, since such formerly reported methods of asymmetric synthesisuse isolated and purified imines, in most cases, problems such as thelimit in their application to imines derived from unstable aliphaticaldehydes, and low asymmetric yield exist.

Therefore, in the present invention, the object is to provide a solutionto the above-mentioned problems of the conventional asymmetricsynthesis, and to provide a novel method which enables the synthesis ofoptically active α-aminonitriles, and further, the synthesis ofoptically active α-amino acids, in high asymmetric yield, without goingthrough imines, even when using unstable aldehydes as startingmaterials.

DISCLOSURE OF INVENTION

The present invention firstly provides, as a means to solve theabove-mentioned problems, a method for producing optically activeα-aminonitriles, which comprises reacting an aldehyde compound, an aminocompound and hydrogen cyanate in the presence of a chiral zirconiumcatalyst obtained by mixing a zirconium alkoxide with at least oneoptically active binaphthol compound.

Also, the present invention secondly provides a method for producingoptically active α-aminonitriles, wherein the optically activebinaphthol compound is at least one compound selected from3,3′-dibromo-1,1′-bi-2-naphthol and 6,6′-dibromo-1,1′-bi-2-naphthol. Theinvention thirdly provides a method for producing optically activeα-aminonitrile, wherein the reaction in conducted in the presence of animidazole compound.

Further, the present invention fourthly provide the method for producingoptically active α-aminonitriles according to any one of the first tothird inventions, wherein an aldehyde compound represented by theformula

R¹CHO

(wherein R¹ represents a hydrocarbon group which may include one or moresubstituents) in reacted with an amino compound represented by theformula

(wherein R² represents a hydrogen atom or a hydrocarbon group which mayinclude a substituent) and hydrogen cyanate to produce an opticallyactive α-aminonitrile represented by the formula

(wherein R¹ and R² are as described above).

Furthermore, the present invention fifthly provides a method forproducing an optically active α-amino acid, which comprises convertingthe cyano group of the optically active α-aminonitrile produced by anyone of the methods of the first to fourth inventions to a carboxyl groupor its derivative.

Also, the invention provides, sixthly, a method for producing anoptically active α-amino acid ester, which comprises converting thecyano group of the α-aminonitrile obtained by the method of the fourthinvention to an ester group, followed by its oxidative decomposition toform an optically active α-amino acid ester represented by the formula

(wherein R and R¹ are hydrocarbon groups which may include one or moresubstituents).

Seventhly, the present invention provides a method for producing apipecolic acid outer represented by the formula

(wherein R is as described above) which comprises the deprotection andprotection of the phenolic hydroxyl group of the α-aminonitrile of thefollowing formula

(wherein R³ represents a protecting group), obtained by the process ofthe fourth invention to form the compound represented by the formula

(wherein R⁴ represents a protecting group), followed by cyclization andesterification to form the ester compound represented by the formula

(wherein R⁴ is an described above, and R represents a hydrocarbon groupwhich my contain one or more substituent), which is then oxidativelydecomposed.

The invention described above enables new development in the long-knownStrecker synthesis. That is, although the Strecker synthesis is a methodfor producing synthetic amino acids wherein α-aminonitriles aresynthesized by the main-component condensation of ammonia, aldehyde andhydrogen cyanate, development of this method as a method of asymmetricsynthesis has been an unexplored task. Under the situation, theinventors of the prevent invention have so far proposed the asymmetricStrecker-type reaction using trialkyltin cyanide as the cyano source(Japanese Patent Provisional Publication No. 255,730/1999). In thepresent invention, the formation of α-aminonitriles by asymmetricsynthesis using hydrogen cyanate as a cyano source is enabled.

In other words, the method for producing the optically activeα-aminonitrile of the present invention enables the realization of theasymmetric synthesis of α-aminonitriles in high yield, directly fromaldehyde compounds, amino compounds and hydrogen cyanate without goingthrough an imine as in formerly known methods.

Further, the present invention also enables the production of opticallyactive α-amino acid in high yield.

BEST MODE FOR CARRYING OUT THE INVENTION

The best mode for carrying out the invention described above in asdescribed bellow.

Basically, in the invention,

(I) an aldehyde compound,

(II) an amino compound, and

(III) hydrogen cyanate (HCN),

are used as the starting materials, reacted in the liquid phase in thepresence of

(IV) a chiral zirconium catalyst to asymmetrically synthesizeα-aminonitrile.

The starting materials, the aldehyde compound (I) and the amino compound(II), maybe aldehydes and amines of various structures, such analiphatic, alicyclic, aromatic, araliphatic or heterocyclic aldehydesand amines. The method of the present invention is applicable tounstable substances such as aliphatic aldehydes which were deemed to beunusable in formerly known asymmetric synthesis of α-aminonitriles,which were performed via imines.

In the aldehyde compound (I), an aldehyde group (—CHO) may be bound toprimary, secondary or tertiary carbon atoms, CH₂—, CH— or C—. Further,the amino compound (II) may be a primary amine or a secondary amine withamino groups such as NH₂ and NH. It is preferable to use a primary amine(—NH₂) compound as the amino compound (II).

The chiral zirconium catalyst (IV) used in the present invention isobtained by mixing a zirconium alkoxide of the following formula

Zr(OR)₄

(wherein R in a hydrocarbon group which may contain one or moresubstituents), with an optically active binaphthol compound. Thehydrocarbon group constituting the alkoxy group (—OR) of the zirconiumalkoxide may be aliphatic, alicyclic aromatic or other hydrocarbongroups, but is preferably an aliphatic hydrocarbon group such as analkyl group. Appropriate examples of such alkyl group include loweralkyl groups such as a methyl group, an ethyl group, an n-propyl group(^(n)Pr), an isopropyl group (^(i)Pr), an n-butyl group (^(n)Bu), anisobutyl group (^(i)Bu), a tert-butyl group (^(t)Bu), an n-pentyl group(^(n)Pent), an isopentyl group (^(i)Pent) and an n-hexyl group(^(n)Hex).

The four alkoxide group (—OR) constituting the zirconium alkoxide(Zr(OR)₄) may all be the same or different.

The optically active binaphthol compound to be mixed with the zirconiumalkoxide may contain appropriate substituents in the naphthalene ring,and more than one optically active binaphthol compounds may be used inthe mixing. Examples of the substituent are a halogen atoms such aschlorine, bromine or fluorine, alkyl groups, alkoxy groups,halo-substituted alkyl groups and alkoxy-substituted alkyl groups.Binaphthol compounds having the same substituents in a symmetricposition on the two naphthalene rings is more preferable. Specificexamples thereof include optically active3,3′-dibromo-1,1′-bi-2-naphthol and optically active6,6′-dibromo-1,1′-bi-2-naphthol.

In the reaction, the zirconium alkoxide and the binaphthol compound maybe added to the reaction system in a premixed state or may be mixed inthe reaction system.

Also, in such asymmetric synthesis, which uses chiral zirconium catalyst(IV) of the present invention, a nitrogen-containing compound,preferably, a nitrogen-containing compound forming a tertiary aminogroup, such as an N-alkyl-substituted imidazole compound, may be presentin the reaction system. The presence of such nitrogen-containingcompound may improve the reactivity.

In the method of asymmetric synthesis of α-aminonitriles of the presentinvention, an appropriate reaction solvent may be used. Examples of suchsolvent include halogenated hydrocarbons, acetonitrile, DMF and DMSO.

The amount of the starting materials and the catalyst used in theasymmetric synthesis are not particularly limited; however, for thestarting materials, the molar ratio, aldehyde compound (I)/aminocompound (II)/HCN(III), may generally be controlled to 1/0.1 to 10/0.1to 10. Further, for the chiral zirconium catalyst (IV), the amount ofthe zirconium alkoxide is preferably 1 to 20 mol %, the amount of thebinaphthol 1 to 50 mol %, and the amount of the nitrogen-containingcompound 40 mol % or less.

In the method for asymmetric synthesis of α-aminonitrile of the presentinvention, the reaction temperature is preferably −70° C. to 30° C.Further, the reaction pressure may be reduced bellow atmosphericpressure or in the rage of atmospheric pressure to 2 atm.

Considering the toxicity of hydrogen cyanate, the reaction is preferablyconducted under low temperature, in the presence of a solvent thatexcels in absorption solubility of hydrogen cyanate, or pressurize by aninert gas such as argon or nitrogen. The starting material, hydrogencyanate (HCN), may be supplied as a gas or may be generated in theliquid phase of the reaction system.

From the method of the present invention, for example, an opticallyactive α-(N-aryl-substituted amino) nitrile compound is obtained in highyield by the reaction of an aldehyde compound (R¹CHO) with a2-hydroxy-6-R²-substituted-aniline and HCN, as stated above.

Such α-aminonitrile enables the selective formation of optically activeα-amino acids, through the decomposition of the cyano group or theconvertion to a carboxyl group or its derivative such as an ester groupthrough esterification.

Some of the optically active α-amino acids are important because theypossess bioactivity or biological activity. Further, selective synthesisof pipecolic acid may also he realized through the prevent invention, asstated earlier.

The invention in illustrated more specifically by referring to thefollowing Examples.

EXAMPLES Example 1

As an optically active α-aminonitrile,1-(2-Hydroxy-6-methyl)amino-3-methylbutane-1-carbonitrile wassynthesized according to the following reaction scheme:

First, 2 equivalents of Zr(O^(t)Bu)₄, 2 equivalents of(R)-6,6′-dibromo-1,1′-bi-2-naphthol ((R)-6-Br-BINOL), 1 equivalent of(R)-3,3′-dibromo-1,1′-bi-2-naphthol((R)-3-Br-BINOL) and 3 equivalents ofN-methylimidazole (NMI) were mixed in toluene to prepare a chiralzirconium catalyst. To this chiral zirconium catalyst (5 mol %, 0.04 M)were added isobutyl aldehyde, 2hydroxy-6-methylaniline and HCN in thepresence of molecular sieve (4 A), at a temperature of −45° C., andstirred for 12 hours (Example 1-1).

The reaction was quenched by the addition of a saturated NaHCO₃ aqueoussolution. The crude product was separated and purified by silica gelchromatography. The optical purity was determined through HPLC with achiral column.

As a result, it was identified that an optically active1-(2-hydroxy-6-methyl)amino-3-methylbutane-1-carbonitrile with anoptical purity of 65 ee % was obtained in a 63% yield.

A reaction similar to that of Example 1-1 was conducted, wherein HCN wasfirst added to the catalyst solution which was then added to a mixtureof the aldehyde and the amine. As a result, the yield was 49%, and theoptical purity was 79 ee % (Example 1-2). Then, this reaction wasconducted by changing the solvent from toluene to dichloromethane. As aresult, the yield became 63%, and the optical purity 85 ee % (Example1-3). Thus, an improvement in the selectivity was observed.

Furthermore, the reaction was conducted in the foregoing manner with thecatalyst concentration changed to 0.01 M, dichloromethane used as thesolvent and the molecular sieve absent. As a result, the yield obtainedwas 99% and the optical purity was 94ee %. Thus, extremely high yieldand selectivity were obtained (Example 1-4).

The above results are shown in Table 1.

TABLE 1 Catalyst Optical Example Molecular Concentration Yield Purity 1-Solvent Sieves M % ee % 1^(a) Toluene 4A 0.04 63 65 2^(b) Toluene 4A0.04 49 79 3^(b) Di- 4A 0.04 63 85 chloromethane 4^(b) Di- none 0.01 9994 chloromethane ^(a)Aldehyde amine and HCN added to catalyst ^(b)HCNadded to catalyst followed by addition of aldehyde and amine

Since these compounds were unstable, the phenolic hydroxyl groupsthereof were methoxylated with 20% methyl iodide-acetone (5 ml) andK₂CO₃ (200 mg) prior to their characterization.

The results of HPLC of the compounds with OH and the characterization ofthe methoxylated compounds are shown in the following table 2:

Examples 1-1 to 1-4 (Compound 2a) Table 2

1-(2-Hydroxy-6-methylphenyl)amino-3-methylbutane-1-carbonitrile (Example1, Compound 2a

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=9/1, flow rate=1.0 ml/min):t_(R)=8.3 min (major), t_(R)=10.2 min (minor).

1-(2-Methoxy-6-methylphenyl)amino-3-methylbutane-1-carbonitrile

¹H NMR (CDCl₃) δ=1.00 (d, 3H, J=6.6 Hz), 1.03 (d, 3H, J=6.6 Hz),1.80-1.83 (m, 2H), 1.99-2.07 (m, 1H), 2.30 (s, 3H), 3.71 (m, 1H), 3.85(s, 3H), 4.20 (t, 1H, J=7.6 Hz), 6.76-6.79 (m, 2H), 6.95 (t, 1H, J=7.8Hz); ¹³C NMR (CDCl₃) δ=17.8, 22.0, 22.5, 24.9, 43.2, 47.4, 55.8, 109.0,120.6, 123.3. 123.5, 130.5, 132.8, 152.0, HRMS calcd for C₁₄H₂₀N₂O (M⁻)232.1576 found 232.1589.

With respect to the chiral zirconium catalyst, it is considered, fromNMR analysis after the removal of the solvent, that during the reactionthe catalyst is present in the structure of the following formula,

wherein the cyano group (CN) does not act as a cyano source for thereaction.

Example 2

The reaction of the following scheme

was conducted in the name manner as in Example 1, using various aldehydecompounds and amino compounds, with 1 to 5 mol % of the chiral zirconiumcatalyst, using dichloromethane as the solvent, at a reactiontemperature of −45° C.

Various α-aminonitriles were obtained in high yield and high selectivityas shown in Table 3.

TABLE 3 Catalyst Optical Example Concentration Yield Purity 2- R¹ R² mol% % ee % 1 Ph H 5 80 86 2 α-Nap H 5 83 85 3 Ph(CH₂)₂ CH₃ 2.5 85 94 4C₈H₁₇ CH₃ 2.5 76 92 5 C₈H₁₇ CH₃ 1 86 84 6 C₈H₁₇ CH₃ 2.5 93  91^(d) 7C₈H₁₇ CH₃ 2.5 95  91^(e) 8 ^(i)Bu CH₃ 5 99 94 9 ^(i)Bu CH₃ 2.5 94 91 10 c-C₆H₁₁ CH₃ 2.5 95 94 11  ^(t)Bu CH₃ 5 quant 86 12  ^(t)Bu CH₃ 2.5 quant 88^(d) ^(d)(O^(n)Pr)₄ used instead of Zr(OtBu)₄ ^(e)(S)-3-Br-BNOL and(S)-6-Br-BINOL used.

Also, by using the chiral zirconium catalyst prepared by usingZr(O^(n)Pr)₄ (zirconium tetra ^(n)propoxide) instead of Zr(O^(t)Bu)₄(zirconium tetra ^(t)butoxide), high selectivity of 91 ee % and 88 ee %were obtained in a 93% yield and quantitative yield.

Further, by using (S)-3-Br-BINOL and (S)-6-Br-BINOL as the opticallyactive binaphthol, excellent results with a yield of 95% and an opticalpurity of 91 ee % were obtained.

The results of HPLC and the characterization of the compounds shown inTable 3 are shown below. For unstable compounds, the characterizationwas conducted for the methoxylated compounds, as in Example 1.

Example 2-1 Table 4

2-(2-Hydroxyphenyl)amino-2-phenylacetonitrile (Example 2-1)

HPLC (Daicel Chiralcel OD, hexane/^(i)PrOH=9/1, flow rate=1.0 ml/min):t_(R)=40.0 min (major), t_(R)=49.7 min (minor). ¹H NMR (CDCl₃) δ=4.43(br, 1H), 5.40 (d, 1H, J=7.2 Hz), 6.72-6.93 (m, 4H), 7.43-7.61 (m, 6H);¹³C NMR (CDCl₃)) ?=50.6, 114.2, 114.9, 118.4, 120.7, 121.5, 127.2,129.3, 129.5, 133.3, 134.0, 144.5.

2-(2-Methoxyphenyl)amino-2-phenylacetonitrile

¹H NMR (CDCl₃) δ=3.81 (s, 3H), 4.67 (d, 1H, J=8.3 Hz), 5.43 (d, 1H,J=8.3 Hz), 6.90-6.95 (m, 4H), 7.42-7.47 (m, 3H), 7.59-7.62 (m, 2H); ¹³CNMR (CDCl₃) δ=49.8, 55.4, 110.0, 111.6, 118.2, 119.6, 121.2, 127.2,129.2, 129.4, 134.1, 134.5, 147.4, HRMS calcd for C₁₅H₁₄N₂O (M⁺)238.1107 found 238.1093.

Example 2-2 Table 5

2-(2-Hydroxyphenyl)amino-2-a-naphthylacetonitrile (Example 2-2)

HPLC (Daicel Chiralpak AD, hexanes/^(i)PrOH=9/1, flow rate=1.0 ml/min):t_(R)=28.5 min (minor), t_(R)=33.7 min (major). ¹H NMR (CDCl₃) δ=4.43(d, 1H, J=7.8 Hz), 5.73 (br, 1H), 5.95 (d, 1H, J=7.8 Hz), 6.67 (d, 1H,J=6.8 Hz), 6.73 (t, 1H, J=6.8 Hz), 6.92 (t, 1H, J=6.8 Hz), 6.98 (d, 1H,J=6.8 Hz), 7.41-7.49 (m, 3H), 7.82-7.92 (m, 4H); ¹³C NMR (CDCl₃) δ=48.5,113.3, 114.9, 118.5, 120.4, 121.5, 122.7, 125.2, 126.2, 126.4, 127.3,128.3, 129.0, 130.1, 130.5, 133.5, 133.9, 144.2.

Example 2-3 (Compound 2b) Table 6

1-(2-Hydroxy-6-methylphenyl)amino-3-phenyl-propane-1-carbonitrile(Example 2-3, Compound 2b)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=19/1, flow rate=1.0 ml/min):t_(R)=30.7 min (major), t_(R)=34.2 min (minor). ¹H NMR (CDCl₃) δ=2.18(s, 3H), 2.19-2.27(m, 2H), 2.80-3.01 (m, 2H), 3.79 (br, 1H), 4.14 (t,1H, J=6.7 Hz), 6.64-6.83 (m, 3H), 7.19-7.34 (m, 5H); ¹³C NMR (CDCl₃)δ=17.6, 32.9, 35.5, 48.3, 113.4, 120.3, 122.1, 123.7, 126.2, 128.2,128.4, 130.9, 130.1, 139.7, 131.3, 139.7, 149.5, HRMS calcd forC₁₇H₁₈N₂O (M⁻) 266.1420 found 266.1419.

Examples 2-4 to 2-7 Table 7

1-(2-Hydroxy-6-methylphenyl)aminonane-1-carbonitrile (Examples 2-4 to2-7)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=19/1, flow rate=1.0 ml/min):t_(R)=10.4 min (major), t_(R)=13.0 min (minor). ¹H NMR (CDCl₃) δ=0.89(t, 3H, J=6.7 Hz), 1.20-1.70 (m, 12H), 1.92 (dt, 2H, J=7.3, 7.7 Hz),2.33 (s, 3H), 4.00 (t, 1H, J=7.3 Hz), 6.70-6.93 (m, 3H); ¹³C NMR (CDCl₃)δ=14.0, 17.7, 22.6, 25.6, 29.0, 29.1, 29.3, 31.7, 34.2, 49.7, 113.4,120.4, 123.0, 125.2, 130.6, 134.5, 150.1, HRMS calcd for C₁₇H₂₆N₂O (M⁺)274.2047, found 274.2045.

Example 2-10 Table 8

2Cyclohexyl-2-(2-hydroxy-6-methylphenyl)aminoacetonitrile (Example 2-10)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=9/1, flow rate=1.0 ml/min):t_(R)=10.0 min (major), t_(R)=13.1 min (minor). ¹H NMR (CDCl₃)?=1.19-1.45 (m, 5H), 1.67-2.08 (m, 6H), 2.33 (s, 3H), 3.84 (d, 1H, J=6.1Hz), 6.70-6.92 (m, 3H); ¹³C NMR (CDCl₃) ?=17.7, 25.6, 25.7, 25.9, 28.6,29.5, 41.4, 55.3, 113.5, 119.6, 123.0, 125.1. 130.9, 132.3, 149.9. HRMScalcd for C₁₅H₂₀N₂O (M⁺) 244.1577, found 244.1577.

Example 2-11 and 2-12 Table 9

2,2-Dimethyl-1-(2-hydroxy-6-methylphenyl)aminopropane-1-carbonitrile(Example 2-11 to 2-12)

HPLC (Daicel Chiralpak AD, hexane/^(i)PrOH=9/1, flow rate=1.0 ml/min):t_(R)=8.2 min (major), t_(R)=16.2 min (minor). ¹H NMR (CDCl₃) δ=1.21 (s,9H), 2.31 (s, 3H), 3.53 (br, 1H), 3.77 (br, 1H), 6.65-6.89 (m, 3H); ¹³CNMR (CDCl₃) δ=17.6, 25.9. 34.8, 59.6, 113.5, 119.5, 122.0, 124.6, 130.9,131.9, 149.5. HRMS calcd for C₁₃H₁₂N₂O (M⁻) 218.1420, found 218.1419.

Example 3

An α-amino acid ester compound was synthesized according to thefollowing scheme:

N-(2-hydroxy-6-methylphenyl)aminonitrile (compounds 2a, 2b), prepared asdescribed in Example 2, was treated with CH₃l and K₂CO₃/acetone at roomtemperature to methoxylate the phenolic OH group, which was thenrefluxed with anhydrous HCl/methanol for 6 hours to convert the cyanogroup into methyl ester group. Consequently, an optically activeN-substituted-α-aminocarboxylic acid methyl ester (compounds 3a, 3b) wasobtained.

Methyl-2-(2-methoxy-6-methyl)phenylamino-4-methyl pentanoate (Compound3a)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=1000/1, flow rate=1.0ml/min): t_(R)=8.1 min (minor), t_(R)=11.0 min (major). ¹H NMR (CDCl₃)δ=0.95 (d, 6H, J=6.4 Hz), 1.58-1.63 (m, 2H), 1.75-1.86 (m, 1H), 2.30 (s,3H), 3.62 (s, 3H), 3.93 (bs, 1H), 4.24 (t, 1H, J=7.2 Hz) 6.68-6.82 (m,3H); ¹³C NMR (CDCl₃) δ=18.2, 22.4, 22.6, 24.8, 43.4, 51.5, 55.6, 57.7,109.1, 121.0, 123.4, 128.3, 134.8, 150.8, 175.7. HRMS calcd forC₁₅H₂₃NO₃ (M⁺) 265.1679, found 265.1688.

Methyl-2-(2-methoxy-6-methyl)phenylamino-4-phenyl butanoate (Compound3b)

HPLC (Daicel Chiralcel OJ, hexane/^(i)PrOH=19/1, flow rate=1.0 ml/min):t_(R)=8.1 min (minor), t_(R)=11.0 min (major). ¹H NMR (CDCl₃) δ=0.95 (d,6H, J=6.4 Hz); 1.58-1.63 (m, 2H), 1.75-1.86 (m, 1H), 2.30 (s, 3H), 3.62(s, 3H), 3.93 (bs, 1H), 4.24 (t, 1H, J=7.2 Hz), 6,68-6.82 (m, 3H); ¹³CNMR (CDCl₃) δ=18.2, 22. HRMS calcd for C₁₉H₂₂NO₂(M⁺) 313.1679, found313.1678.

Compound 3a was oxidatively decomposed using cerium ammonium nitrate(CAN) to obtain leucine methyl ester (compound 4a) as the correspondingN-free-amino acid ester.

A more stable hydrochloride of compound 4a was easily obtained bytreatment with HCl/methanol at a temperature of 0° C. The yield fromcompound 2a was 70%.

The optical purity of compound 4a was as high as 99 ee % or more.

The characterization of compound 4a is shown in table 10.

Compound 3a Table 10

Leucine methyl ester (N-free amino ester) (Compound 4a)

¹H NMR δ=0.86-0.95 (m, 6H), 1.40-1.62 (m, 2H), 1.73-1.82 (m, 1H), 2.27(bs, 2H), 3.52 (s, 3H); ¹³C NMR δ=21.8, 22.9, 24.7, 43.8, 51.9, 52.7,176.8. HRMS calcd for C₇H₁₅NO₂ (M⁺) 145.1104, found 145.1103.

Further, the results of HPLC after benzoylation are as follows.

Leucine methyl ester (after benzoylation)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH=19/1, flow rate 1.0 ml/min);t_(R)=19.1 (minor), t_(R)=26.7 (major).

In the same manner, β-phenylalanine methyl ester of compound 4b wasobtained from compound 3b.

The identification proportion and HPLC results are as follows:

β-Phenylalanine methyl ester (N-free amino ester) (Compound 4b)

¹H NMR δ=1.75 (br, 2H), 1.83-1.90 (m, 1H), 2.04-2.11 (m, 1H), 2.68 -2.78(m, 2H), 3.47 (br, 1H), 3.71 (s, 3H), 7.18-7.30 (m, 5); ¹³C NMR δ=31.9,36.4, 51.9, 53.9, 126.0, 128.39, 128.42, 141.2, 176.4. HRMS calcd forC₁₁H₁₅NO₂ (M⁻) 193.1104, found 193.1102.

β-Phenylalanine methyl ester (after Benzoylation)

HPLC (Daicel Chiralcel OD, hexane/^(i)PrOH=9/1, flow rate 1.0 ml/min);t_(R)=24.4 (major), t_(R)=29.1 (minor).

Example 4

A D-pipecolic acid methyl ester was synthesized according to thefollowing scheme:

The results of HPLC and the identification properties of the compoundsin the respective reaction steps are as follows.

Compound 5

5-tert-Butyldimethylsiloxy-1-(2-hydroxy-6-methylphenyl)aminopentane-1-carbonitrile (Compound 5)

HPLC (Daicel Chiralpak AS, hexane/^(i)PrOH 24/1, flow rate=0.5 ml/min):t_(R)=13.5 min (major), t_(R)=15.3 min (minor). ¹H NMR (CDCl₃) δ=0.00(s, 6H), 0.84 (s, 9H), 1.50-1.70 (m, 4H), 1.83-1.87 (m, 2H), 2.23 (s,3H), 3.59 ( t, 2H, J=5.6 Hz), 3.99 (t, 1H, J=7.0 Hz), 6.59-7.28 (m, 3H);¹³C NMR (CDCl₃) δ=−5.4, 17.7, 18.3, 22.0, 25.9, 31.9, 33.8, 49.4, 62.6,113.4, 120.3, 122.8, 124.7, 130.8, 132.0, 149.8. HRMS calcd forC₂₀H₃₄N₂O₂ ²⁰Si (M⁻) 362.2391, found 362.2390.

Compound 6

5-Hydroxy-1-(2-methoxy-6-hydroxyphenyl)aminopentane carbonitrile(Compound 6)

¹H NMR (CDCl₃) δ=1.55-1.72 (m, 4H), 1.88-1.98 (m, 2H), 2.27 (s, 3H),3.62 (t, 2H, J=5.9 Hz), 3.82 (s, 3H), 4.12 (t, 1H, J=6.9 Hz), 6.74-7.35(m, 3H); ¹³C NMR (CDCl₃) δ=17.6, 21.8, 31.7, 33.7, 48.9, 55.7, 61.8,108.9, 120.2, 123.2, 123.5, 130.5, 132.6, 152.0.

Compound 7

N-(2-Methoxy-6-methylphenyl)-pipecolic acid methyl ester(Compound 7)

¹H NMR (CDCl₃) δ=1.52-1.60 (m, 2H), 1.68-1.82 (m, 4H), 2.29 (s, 3H),3.51 (t, 2H, J=6.6 Hz), 3.66 (s, 3H), 3.81 (s, 3H), 4.19 (t, 1H, J=7.5Hz), 6.69-6.82 (m, 3H); ¹³C NMR (CDCl₃) δ=18.2, 22.8, 32.2, 33.0, 44.6,51.7, 55.6, 58.8, 109.0, 121.1, 123.4, 128.4, 134.5, 150.8, 175.0, HRMScalcd for C₁₅H₂₁N₂O₃ (M⁻) 263.1522, found 263.1521.

Compound 8

Pipecolic acid methyl ester (Compound 8)

¹H NMR (CDCl₃) δ=1.55-1.76 (m, 2H), 1.78-1.82 (m, 4H), 2.97 (br, 1H),3.45-3.52 (m, 1H), 3.54 (t, 2H, J=6.7 Hz), 3.74 (s, 3H); ¹³C NMR (CDCl₃)δ=23.0, 29.7, 32.2, 44.6, 52.1, 52.9, 169.7.

INDUSTRIAL APPLICABILITY

As has ben described in detail above, according to the presentinvention, the asymmetric synthesis of α-aminonitriles and α-amino acidswith high yield and high stereoselectivity is enabled, without goingthrough imines, even when using unstable aldehyde as the startingmaterial, as in the conventional methods.

What is claimed is:
 1. A method for producing optically active α-aminonitrile, which comprises reacting an aldehyde compound, an amino compound and hydrogen cyanate in the presence of a chiral zirconium catalyst obtained by mixing a zirconium alkoxide with at least one optically active binaphthol compound.
 2. The method according to claim 1, wherein the optically active binaphthol compound in at least one compound selected from 3,3′-dibromo-1,1′-bi-2-naphthol and 6,6′-dibromo-1,1′-bi-2-naphthol.
 3. The method according to claim 1, wherein the reaction is conducted in the presence of an imidazole compound.
 4. The method according to claim 1, wherein an aldehyde compound represented by the formula R¹CHO (wherein R¹ represents a hydrocarbon group which may contain one or more substituent) is reacted with an amino compound represented by the formula

(wherein R² represents a hydrogen atom or a hydrocarbon group which may contain one or more substituents) and hydrogen cyanate to produce an optically active α-aminonitrile represented by the formula

(wherein R¹ and R² are as described above).
 5. A method for producing optically active α-amino acid, which comprises converting the cyano group of the optically active α-aminonitrile produced by the method of claim 1 to a carboxyl group or its derivative.
 6. A method for producing an optically active α-amino acid ester, which comprises converting the cyano group of the α-aminonitrile obtained by the method of claim 4 to an eater group, followed by its oxidative decomposition to form an optically active α-amino acid ester represented by the formula

(wherein R and R¹ represent hydrocarbon groups which may contain one or more substituents).
 7. A method for producing a pipecolic acid ester represented by the formula

(wherein R is as described above), which comprises the deprotection and protection of the phenolic hydroxyl group of the α-aminonitrile

(wherein R³ represents a protecting group), obtained by the method of claim 4, to form a compound represented by the formula

(wherein R⁴ represents a protecting group), followed by its cyclization and esterification to form an ester compound represented by the formula

(wherein R⁴ is as defined above and R represents a hydrocarbon group which may contain one or more substituent) followed by its oxidative decomposition. 